Pharmaceutically useful imidazopyridines

ABSTRACT

The invention relates to novel compounds of the formula I ##STR1## and the therapeutic use thereof.

This application is a 371 of PCT/EP94/00335 filed Feb. 7, 1994.

FIELD OF THE INVENTION

The invention relates to novel imidazopyridines which are intended foruse in the pharmaceutical industry as active substances for producingpharmaceuticals.

BACKGROUND OF THE INVENTION

European Patent Application EP-A-O 033 094 describesimidazo[1,2-a]pyridines which have in position 8 an aryl substituentwhich is preferably a phenyl, thienyl or pyridyl radical or a phenylradical which is substituted by chlorine, fluorine, methyl, tert.-butyl,trifluoromethyl, methoxy or cyano. Aryl radicals mentioned asparticularly interesting in EP-A-0 033 094 are the radicals phenyl, o-or p-fluorophenyl, p-chlorophenyl and 2,4,6-trimethylphenyl, of whichthe radicals phenyl, o- or p-fluorophenyl and 2,4,6-trimethylphenyl areparticularly preferred. European Patent Applications EP-A-0 204 285,EP-A-0 228 006, EP-A-0 268 989 and EP-A-0 308 917 describeimidazo[1,2-a]pyridines which have in position 3 an unsaturatedaliphatic radical, in particular a (substituted) alkynyl radical.European Patent Application EP-A-0 266 890 describesimidazo[1,2-a]pyridines which are substituted in position 8 by analkenyl, alkyl or cycloalkylalkyl radical.

DESCRIPTION OF THE INVENTION

It has now been found that the compounds which are described in detailhereinafter and which differ from the compounds of the prior art, inparticular by the substitution in position 3 or 8, have surprising andparticularly advantageous properties.

The invention relates to compounds of the formula I (see the end of thisspecification)

in which

R0 denotes methyl or hydroxymethyl,

R1 denotes 1-4C-alkyl,

R2 denotes 1-4C-alkyl,

R3 denotes 1-4C-alkoxy and

A denotes O (oxygen) or NH,

and the salts thereof.

1-4C-alkyl represents straight-chain or branched alkyl radicals with 1to 4 carbon atoms. Examples which may be mentioned are the butyl,iso-butyl, sec.-butyl, tert.-butyl, propyl, isopropyl, ethyl and, inparticular, the methyl radical.

1-4C-alkoxy represents an oxygen atom to which one of the abovementioned1-4C-alkyl radicals is bonded. The methoxy radical is preferred.

Suitable salts for compounds of the formula I are preferably all acidaddition salts. Particular mention may be made of the pharmacologicallycompatible salts of the inorganic and organic acids customarily used inpharmaceutical technology. Pharmacologically incompatible salts whichmay, for example, be the initial products of the processes for thepreparation of the compounds according to the invention on an industrialscale are converted into pharmacologically compatible salts by processesknown to the skilled worker. Suitable as such are water-soluble andwater-insoluble acid addition salts with acids, such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed for the preparation of the salts in a ratio of amountswhich is equimolar or different therefrom--depending on whether the acidis mono- or polybasic and depending on which salt is required.

Examples of preferred compounds which may be mentioned are the compounds3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methyl-imidazo[1,2-a]pyridine,3-hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridine,8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridineand8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridineand the salts thereof.

The invention further relates to a process for the preparation of thecompounds of the formula I and the salts thereof. The process comprises

a) for the preparation of the compounds of the formula I, in which R0denotes hydroxymethyl, reducing compounds of the formula II (seeattached sheet of formulae), in which R1, R2, R3 and A have theabovementioned meanings, or comprises

b) for the preparation of the compounds of the formula I, in which R0denotes methyl, reacting compounds of the formula III (see attachedsheet of formulae), in which R1 and A have the abovementioned meanings,with compounds of the formula IV (see attached sheet of formulae), inwhich R2 and R3 have the abovementioned meanings and X denotes asuitable leaving group, or comprises

c) for the preparation of the compounds of the formula I, in which R0denotes methyl, reacting compounds of the formula V (see attached sheetof formulae), in which R1, R2 and A have the abovementioned meanings,with compounds of the formula VI (see attached sheet of formulae),wherein R3 has the abovementioned meanings and Y denotes a suitableleaving group,

and, if required, subsequently converting the resulting compounds I intothe salts thereof, or comprises, if required, subsequently liberatingthe compounds I from the resulting salts of the compounds I.

The reduction of the compounds II is carried out in a manner familiar tothe skilled worker. It takes place in inert solvents, for example loweraliphatic alcohols, for example by use of suitable hydrides, such assodium borohydride, if desired with the addition of water.

The reaction of the compounds III with the compounds IV is carried outin a manner familiar to the skilled worker, for example by analogousApplication of processes such as those described in European PatentApplications EP-A-0 033 094 or EP-A-0 308 917. A suitable leaving groupis, for example, a halogen atom (preferably chlorine or bromine) or amethanesulfonyloxy group. The reaction is carried out advantageously inthe presence of a base (e.g. of an inorganic hydroxide, such as sodiumhydroxide, or of an inorganic carbonate, such as potassium carbonate, orof an organic nitrogen base, such as triethylamine, pyridine, collidinor 4-dimethylaminopyridine), in which the course of the reaction can beassisted by the addition of catalysts, such as alkali iodide ortetrabutylammonium bromide.

The reaction of the compounds V with the compounds VI is also carriedout in a manner familiar to the skilled worker as it is customary forthe preparation of aromatic urethans, preferably by reacting thecompounds V with haloformiates (Y=halogen), such as chloroformiates, ininert solvents. The reaction is advantageously carried out in thepresence of an acid binding agent (proton acceptor). As protonacceptors, alkali metal carbonates (such as potassium carbonate) orhydrogen carbonates (such as sodium hydrogen carbonate), or tertiaryamines (such as triethylamine) may be mentioned for example.

The skilled worker is aware because of his expert knowledge of thespecific reaction conditions required for carrying out the process.

The substances according to the invention are isolated and purified in amanner known per se, for example in such a way that the solvent isremoved by distillation in vacuo, and the resulting residue isrecrystallized from a suitable solvent or subjected to one of theconventional purification methods such as, for example, columnchromatography on suitable support material.

Acid addition salts are obtained by dissolving the free base in asuitable solvent, for example in a chlorinated hydrocarbon, such asmethylene chloride or chloroform, or a lower aliphatic alcohol (ethanol,isopropanol), a ketone, such as acetone, or an ether, such astetrahydrofuran or diisopropylether, which contains the required acid orto which the required acid is subsequently added.

The salts are isolated by filtration, reprecipitation, precipitationwith a non-solvent for the addition salt or by evaporating off thesolvent. Resulting salts can be converted by rendering alkaline, forexample with aqueous ammonia solution, into the free bases which can, inturn, be converted into acid addition salts. It is possible in this wayto convert pharmacologically incompatible acid addition salts intopharmacologically compatible acid addition salts.

The starting compounds II can be prepared in a manner known per se, forexample by reacting the compounds VII with the compounds VIII (seeattached sheet of formulae) in which R1, R2, R3 and A have theabovementioned meanings, and X is a suitable leaving group, for examplea halogen atom (preferably chlorine or bromine), or by analogousapplication of processes, such as those described, for example, inEuropean Patent Applications EP-A-0 033 094 or EP-A-0 308 917.

The starting compounds III are known from European Patent ApplicationEP-A-0 299 470, the starting compounds IV from European PatentApplication EP-A-0 308 917.

The starting compounds V can be prepared in a manner known per se fromthe corresponding nitro compounds by reduction. The nitro compoundsthemselves can be prepared from the compounds III and appropriate nitrocompounds corresponding with the compounds IV.

The following examples serve to explain in detail the preparation of thecompounds according to the invention. In particular, the examples serveto exemplary describe the reactions according to the process variants a,b and c as well as the preparation of selected starting compounds.Likewise, further compounds of the formula I as well as further startingcompounds, the preparation of which is not described explicitly, can beprepared in an analogous manner or in a manner familiar to the skilledworker by applying usual process techniques. The abbreviation RT standsfor room temperature, h stands for hour(s), m.p. for melting point, dec.for decomposition.

EXAMPLES 1.3-Formyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine

A suspension of 400 mg of commercial 80% sodium hydride in 10 ml of drytetrahydrofuran is added to a solution of 2 g of8-amino-3-formyl-2-methylimidazo[1,2-a]pyridine in 40 ml of drytetrahydrofuran at RT. Brief heating at 50° C. is followed by vigorousevolution of gas. After the evolution of gas is complete, the mixture iscooled to 0° C., and a solution of 3.9 g of2-methoxycarbonylamino-6-methylbenzyl bromide in 40 ml of drytetrahydrofuran is added dropwise. The mixture is again heated to 50° C.and kept at this temperature for 3 h. It is then poured into ice-water,neutralized with a little dilute hydrochloric acid and extracted fourtimes with ethyl acetate. The collected organic phases are washed withwater and dried over sodium sulfate. The solvent is stripped off invacuo, and the dark brown viscous residue is chromatographed on silicagel (ethyl acetate:petroleum ether=1:1 as eluent). Recrystallizationfrom isopropanol results in 2.5 g of the title compound of m.p.188°-190° C. (dec.).

2.3-Hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridine

2 g of3-formyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methylimidazo[1,2-a]pyridineare suspended in 30 ml of methanol at RT, 0.2 g of sodium borohydride isadded in portions, and the mixture is stirred at RT for 1 h.Subsequently, half the solvent is stripped off in vacuo, the residue ispoured into ice-water, and the mixture is neutralized with a few dropsof dilute hydrochloric acid and extracted four times with ethyl acetate.The collected organic phases are washed with water and dried over sodiumsulfate. The solvent is stripped off in vacuo. The remaining yellowishresidue completely crystallizes after some time. Recrystallization fromethyl acetate results in 1.3 g of the title compound of m.p. 170°-172°C.

3.3-Formyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridine

2.6 g of 3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine are dissolvedin 50 ml of dry acetonitrile with exclusion of moisture at 50° C. and,after cooling to RT, 2.8 g of commercial potassium fluoride (50% byweight) on kieselguhr (for example Celite®) are added. A solution of 3.6g of 2-methoxycarbonylamino-6-methylbenzyl bromide in 50 ml of dryacetonitrile is added dropwise, and the mixture is heated at 70° C. for6 h. After cooling to RT, the mixture is poured into ice-water, adjustedto pH 9 with a few drops of 6N sodium hydroxide solution and extractedwith ethyl acetate. The collected organic phases are washed with waterand dried over sodium sulfate. Stripping off the solvent in vacuo andstirring in a little cold methanol result in 3.2 g of the title compoundof m.p. 196°-198° C.

4.3-Hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridine

In analogy to Example 2, 2.1 g of the title compound of m.p. 185°-187°C. are obtained from 3 g of3-formyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridineand 400 mg of sodium borohydride.

5.8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

4.5 g of sodium iodide and 6.63 g of dry sodium carbonate are added to asolution of 4.03 g of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine and6.41 g of 2-methoxycarbonylamino-6-methyl-benzyl chloride in 400 ml ofdry acetone, and the mixture is heated under reflux for 6 h. Aftercooling to RT, 400 ml of water are added and the acetone is distilledoff in a water jet vacuum. The aqueous residue is then extracted threetimes with each time 200 ml of ethyl acetate. The combined organicextracts are washed with 300 ml of water, dried over magnesium sulfateand then concentrated. The residue is purified by chromatography onsilica gel (toluene/dioxan=9:1 as eluent). The fractions with R_(f) =0.2are concentrated and then recrystallized from diisopropyl ether. 4.71 g(56%) of the title compound of m.p. 136°-138° C. are isolated.

a) By reacting the title compound, dissolved in acetone, with 12Nhydrochloric acid, the hydrochloride of the title compound of m.p.211°-212° C. (dec.) is obtained.

b) By reacting the title compound, dissolved in tetrahydrofuran, withmethanesulfonic acid, the methanesulfonate of the title compound of m.p.181°-182° C. (dec.) is obtained.

c) By reacting the title compound, dissolved in acetone, with fumaricacid, the hemifumarate of the title compound of m.p. 191°-192° C. (dec.)is obtained.

6.8-(2-Methoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine

A solution of 9.5 g of 2-methoxycarbonylamino-6-methylbenzyl chloride in150 ml of dry acetonitrile is added dropwise at RT to a suspension of7.2 g of 8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine in 130 ml of dryacetonitrile, to which 8 g of commercial potassium fluoride (50% byweight) in kieselguhr (for example Celite®) has been added. The mixtureis heated at 70° C. for 9 h. After cooling to RT, the mixture is pouredinto 1 l of ice-water and extracted three times with ethyl acetate. Thecollected organic phases are washed with distilled water and dried oversodium sulfate. After stripping off the organic solvent in vacuo, theprecipitating residue is filtered off, washed with a little ethylacetate and ether and dried. After recrystallization from isopropanol,2.2 g of the title compound of m.p. 176°-177° C. are obtained.

7. 8-(6-Methyl-2-nitrobenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

Sodium iodide (15.0 g) and sodium carbonate (31.0 g) are added to asolution of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (14.7 g) and6-methyl-2-nitrobenzylchloride (18.6 g) in acetone (100 ml) at RT andare heated to reflux for 6 h. After cooling to RT and evaporation of thesolvent, the residue is dissolved in a mixture of ethyl acetate (200 ml)and water (200 ml), and the organic phase is separated off. After threefurther extractions with ethyl acetate (100 ml) the combined organiclayers are dried over magnesium sulfate and concentrated to a volume of80 ml. 12.1 g of the title compound crystallize as a faintly yellowsolid. The mother liquor is evaporated and the residue is purified bychromatography on silica gel (toluene/dioxane=6:1 as eluent) to yieldadditional 14 g of crystalline material. After recrystallization of bothfractions from ethyl acetate, 21.5 g (76%) of the title compound of m.p.160°-162° C. are isolated.

8.8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

The title compound is prepared according to the procedure described forexample 1 starting from 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (4.8g), 2-tert-butoxycarbonylamino-6-methylbenzylchloride (9.2 g), sodiumiodide (5.5 g) and sodium carbonate (8.0 g) in acetone (250 ml).Purification by chromatography on silica gel (toluene/dioxane 20:1 aseluent) and crystallization from diisopropyl ether yield 7.1 g (62%) ofm.p. 149°-152° C.

9.8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

The title compound is prepared according to the procedure described forexample 7 starting from 2,3-dimethyl-8-hydroxy-imidazo[1,2-a]pyridine(1.6 g), 2-tert-butoxycarbonylamino-6-methylbenzylchloride (3.1 g),sodium iodide (1.8 g) and sodium carbonate (2.7 g) in acetone (350 ml).Purification by chromatography on silica gel (toluene/dioxane 5:1 aseluent) and crystallization from cyclohexane yield 3.0 g (78%) of m.p.128°-131° C.

10.8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine

The title compound is prepared according to the procedure described forexample 7 starting from 8-amino-3-formyl-2-methylimidazo[1,2-a]pyridine(4.0 g), 2-tert-butoxycarbonylamino-6-methylbenzylchloride (7.0 g),sodium iodide (4.1 g) and sodium carbonate (6.1 g) in acetone (250 ml).Purification by chromatography on silica gel (toluene/dioxane 9:1 aseluent) and crystallization from diisopropyl ether yield 7.3 g (81%) ofm.p. 210°-212° C.

11.8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine

a) 4.77 g of 8-benzyloxy-2-methylimidazo[1,2-a]pyridine are stirred in aVilsmeier mixture of 20 ml of dimethylformamide and 2.3 ml of phosphorylchloride for 2.5 h at 60° C., and are worked up mit ice/water andpotassium hydrogen carbonate in a usual manner.8-Benzyloxy-2-methylimidazo[1,2-a]pyridine-3-carboxaldehyde of m.p.105°-106° C. (from diisopropylether) is obtained, which is debenzylatedaccording to Kaminski et al., J. Med. Chem. 28, 876 (1985), method H, toyield 3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine of m.p.251°-252° C.

b) The title compound is prepared according to the procedure describedfor example 7 starting from3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine (2.4 g),2-tert-butoxycarbonylamino-6-methylbenzylchloride (4.2 g), sodium iodide(2.5 g) and sodium carbonate (3.7 g) in acetone (400 ml). Purificationby crystallization from diisopropyl ether/ethyl acetate yield 4.4 g(80%) of m.p. 189°-191° C.

12. 8-(2-Amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

Method A:

A solution of8-(6-methyl-2-nitrobenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (61g) in methanol (5.5 l) is treated with 15 g of palladium on charcoal(5%) catalyst and hydrogenated at atmospheric pressure for 1.5 h at RT.The catalyst is filtered off and the solvent is evaporated. The residueis dissolved in boiling ethyl acetate (2.7 l). After cooling to RT, 51 g(82%) of the title compound of m.p. 206°-208° C. are isolated.

Method B:

8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo-[1,2-a]pyridine(6.7 g) is added portionwise to a mixture of trifluoroacetic acid (30ml) and anisole (3 ml) at 25°-30° C. After stirring for 30 minutes at RTthe solution is added to ice-water (100 ml) and then treated with 6Nsodium hydroxide solution (75 ml). The precipitate is filtered andpurified by chromatography on silica gel (toluene/dioxane=8:1 aseluent). After crystallization from ethyl acetate, 3.1 g (62%) of thetitle compound of m.p. 206°-208° C. are isolated.

13.8-(2-Amino-6-methylbenzyloxy)-3-formyl-2-methylimidazo[1,2-a]pyridine

Starting from8-(2-tert.-butoxy-carbonylamino-6-methylbenzyloxy)-3-formyl-2-methylimidazo[1,2-a]pyridine(5.0 g) and trifluoroacetic acid (40 ml) and by using the proceduredescribed for example 12 (method B), 3.57 g (96%) of the title compoundof m.p. 144°-150° C. (dec.) are obtained.

14.8-(2-Ethoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

Ethyl chloroformiate (0.65 g) dissolved in dichloromethane (10 ml) isadded dropwise to a solution of8-(2-Amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.98g) in dichloromethane (50 ml) and stirred for 18 h at RT. The solutionis then extracted with saturated aqueous sodium bicarbonate solution (40ml), washed with water (40 ml) and evaporated. The residue isrecrystallized from ethyl acetate/diisopropyl ether. 0.32 g (26%) of thetitle compound of m.p. 208°-210° C. (dec.) are isolated.

15.8-(2-Isobutoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

The title compound is prepared according to the procedure described forexample 14 starting from isobutyl chloroformiate (0.3 g) and8-(2-Amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.56g) in dichloromethane (50 ml). 0.22 g (29%) of the title compound ofm.p. 144°-146° C. are isolated.

16.8-(2-Isobutoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine

The title compound is prepared according to the procedure described forexample 14 starting from isopropyl chloroformiate (1.5 g) and8-(2-Amino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.98g) in dichloromethane (50 ml). 0.32 g (25%) of the title compound areisolated.

17.8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine

The title compound is prepared according to the procedure described forexample 2 starting from8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine(0.15 g) and sodium borohydride (15 mg) in methanol. 0.12 g of the titlecompound of m.p. 102°-104° C. are isolated.

18.8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine

The title compound is prepared according to the procedure described forexample 2 starting from8-(2-tert-Butoxycarbonylamino-6-methylbenzyloxy)-3-formyl-2-methylimidazo[1,2-a]pyridine(0.20 g) and sodium borohydride (19 mg) in methanol. 0.17 g of the titlecompound of m.p. 140°-142° C. are isolated.

Industrial applicability

The compounds of the formula I and their salts have valuablepharmacological properties which make them industrially utilizable. Theyexhibit, in particular, a pronounced inhibition of gastric acidsecretion and an excellent protective action on the stomach andintestines of warm-blooded species. In this respect the compoundsaccording to the invention are distinguished by a great selectivity ofaction, a comparatively long duration of action, a good enteralefficacy, the absence of significant side effects and a wide therapeuticrange.

By "protection of the stomach and intestines" is meant in thisconnection the prevention and treatment of gastrointestinal disorders,especially gastrointestinal inflammatory disorders and lesions (such as,for example, gastric ulcer, duodenal ulcer, gastritis, functionalgastropathy due to hyperacidity or drugs) which may be caused, forexample, by microorganisms (for example Helicobacter pylori), bacterialtoxins, drugs (for example certain antiinflammatory and antirheumaticagents), chemicals (for example ethanol), gastric acid or stresssituations.

In their excellent properties, the compounds according to the inventionsurprisingly prove to be distinctly superior, in various models in whichthe antiulcerogenic and the antisecretory properties are determined, tothe known compounds of the prior art. Because of these properties, thecompounds of the formula I and their pharmacologically compatible saltsare outstandingly suitable for use in human and veterinary medicine,where they are particularly used for the treatment and/or prophylaxis ofdiseases of the stomach and/or intestine.

The invention therefore further relates to the compounds according tothe invention for use for the treatment and/or prophylaxis of theabovementioned disorders.

The invention likewise embraces the use of the compounds according tothe invention for the production of pharmaceuticals which are employedfor the treatment and/or prophylaxis of the abovementioned disorders.

The invention furthermore embraces the use of the compounds according tothe invention for the treatment and/or prophylaxis of the abovementioneddisorders.

The invention further relates to the pharmaceuticals which contain oneor more compounds of the formula I and/or their pharmacologicallycompatible salts.

The pharmaceuticals are produced by processed which are known per se andfamiliar to the skilled worker. As pharmaceuticals, thepharmacologically active compounds (=active substances) according to theinvention are employed either as such or, preferably, in combinationwith suitable pharmaceutical ancillary substances or vehicles in theform of tablets, coated tablets, capsules, suppositories, plasters (forexample as TTS), emulsions, suspensions or solutions, wherein thecontent of active substance is advantageously between 0.1 and 95%, andwherein by appropriate choice of the ancillary substances and vehicles apharmaceutical formulation (e.g. a sustained release formulation or anenteric formulation) can be obtained which fits exactly to the activesubstance and/or to the desired onset of effects.

The skilled worker is aware because of his expert knowledge whichancillary substances and vehicles are suitable for the requiredpharmaceutical formulations. Besides solvents, gel formers, suppositorybases, tablet ancillary substances and other active substance vehicles,it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoam agents, flavour correctives, preservatives,solubilizers, colorants or, in particular, permeation promoters andcomplexing agents (for example cyclodextrins).

The active substances can be administered orally, parenterally orpercutaneously.

In general, it has proven advantageous in human medicine to administerthe active substance or substances on oral administration in a dailydose of about 0.01 to about 20, preferably 0.05 to 5, in particular 0.1to 1.5 mg/kg of body weight, where appropriate in the form of aplurality, preferably 1 to 4, individual administrations to achieve therequired result. In the case of parenteral treatment it is possible touse similar or (especially for intravenous administration of the activesubstances) as a rule lower dosage. The skilled worker is easily ablebecause of his expert knowledge to establish the optimal dosage and modeof administration of the active substances required in each case.

If the compounds and/or salts according to the invention are to beemployed for the treatment of the abovementioned disorders, thepharmaceutical preparations can also contain one or morepharmacologically active constituents from other groups ofpharmaceuticals, such as antacids, for example aluminium hydroxide,magnesium aluminate; tranquilizers such as benzodiazepines, for examplediazepam; spasmolytics such as, for example, bietamiverine, camylofin;anticholinergics such as, for example, oxyphencyclimine, phencarbamide;local anesthetics such as, for example, tetracaine, procaine; whereappropriate also enzymes, vitamins or amino acids.

Particularly noteworthy in this connection is the combination of thecompounds according to the invention with drugs which inhibit acidsecretion, such as, for example, H₂ blockers (for example cimetidine,ranitidine), H⁺ /K⁺ ATPase inhibitors (for example omeprazole,pantoprazole), or furthermore with so-called peripheral anticholinergics(for example pirenzepine, telenzepine) and with gastrin antagonists withthe aim of enhancing the principal action in an additive orsuperadditive sense and/or eliminating or reducing the side effects, orfurthermore the combination with substances with antibacterial activity(such as, for example, cephalosporins, tetracyclines, nalidixic acid,penicillins or else bismuth salts) to control Helicobacter pylori.

Pharmacology

The excellent protective action on the stomach and the action inhibitinggastric acid secretion by the compounds according to the invention canbe demonstrated in investigations on animal experimental models. Thecompounds according to the invention investigated in the model detailedhereinafter have been provided with numbers which correspond to thenumbers of these compounds in the examples.

Examination of the secretion-inhibiting action on the perfused ratstomach

The effect of the compounds according to the invention afterintraduodenal administration on the acid secretion stimulated bypentagastrin in the perfused rat stomach in vivo is represented in thefollowing Table 1.

                  TABLE 1                                                         ______________________________________                                                   Dose                                                                          (μmol/kg)                                                                           Inhibition of acid secretion                              No.        i.d.     (%)                                                       ______________________________________                                        2          6        100                                                       4          10       100                                                       5          3        100                                                       6          3        100                                                       ______________________________________                                    

Method

Anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kg i.m. urethane)underwent tracheotomy and then opening of the abdomen by a medianepigastric incision, and fixation of a PVC catheter transorally in theesophagus and another via the pylorus in such a way that the ends of thetubes just projected into the lumen of the stomach. The catheter leadingout of the pylorus led via a lateral opening in the right abdominal wallto the outside.

After thorough irrigation (about 50-100 ml) of the stomach,physiological NaCl solution at 37° C. was passed through continuously(0.5 ml/min, pH 6.8-6.9; Brun-Unita I). The effluate was collected (25ml measuring cylinder) at intervals each of 15 min and underwentdetermination of the pH (pH meter 632, glass electrode EA 147;Diameter=5 mm, Metrohm) and, by titration against a freshly prepared0.01N NaOH to pH 7 (Dosimat 655 Metrohm), of the secreted HCl.

Gastric secretion was stimulated by continuous infusion of 1 μg/kg(=1.65 ml/h) i.v. pentagastrin (left femoral vein) about 30 min afterthe end of the operation (that is to say after determination of 2preliminary fractions). The substances to be tested were administeredintraduodenally in a liquid volume of 1 ml/kg 60 min after the start ofthe continuous infusion of pentagastrin.

The body temperature of the animals was kept constant at 37.8°-38° C. byinfrared irradiation and a heated cushion (automatic stepless controlvia rectal temperature sensor).

The dose which led to a maximum inhibition of acid secretion by 100% isindicated in the Table. ##STR2##

We claim:
 1. A compound of formula Iin which R0 denotes methyl orhydroxymethyl, R1 denotes 1-4C-alkyl, R2 denotes 1-4C-alkyl, R3 denotes1-4C-alkoxy and A denotes O (oxygen) or NH,or a salt thereof.
 2. Acompound of formula I according to claim 1, wherein R0 denotes methyl.3. A compound of formula I according to claim i, wherein R0 denoteshydroxymethyl.
 4. A compound according to claim 1 selected from thegroup consistingof3-Hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzylamino)-2-methyl-imidazo[1,2-a]pyridine,3-Hydroxymethyl-8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-imidazo[1,2-a]pyridine,8-(2-Methoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine,8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,8-(2-tert-Butoxycarbonylamino-6-methylbenzyloxy)-2,3-dimethylimidazo[1,2-a]pyridine,8-(2-Ethoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,8-(2-Isobutoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,8-(2-Isopropoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,8-(2-tert-Butoxycarbonylamino-6-methylbenzylamino)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridineand8-(2-tert-Butoxycarbonylamino-6-methylbenzyloxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridineora salt thereof.
 5. The compound of claim 1:8-(2-Methoxycarbonylamino-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine,or a salt thereof.
 6. A process for the preparation of a compound offormula I as claimed in claim 1 and a salt thereof, which comprisesa)for the preparation of a compound of formula I, in which R0 denoteshydroxymethyl, reducing compound of formula II ##STR3## in which R1, R2,R3 and A have the meanings given in claim 1, or comprises b) for thepreparation of a compound of formula I, in which R0 denotes methyl,reacting a compound of formula III ##STR4## in which R1 and A have themeanings given in claim 1, with a compound of formula IV ##STR5## inwhich R2 and R3 have the meanings given in claim 1 and X denotes asuitable leaving group, or comprises c) for the preparation of acompound of formula I, in which R0 denotes methyl, reacting a compoundof formula V ##STR6## in which R1, R2 and A have the meanings given inclaim 1, with compound of formula VI

    R3--CO--Y                                                  (VI)

wherein R3 has the meaning given in claim 1 and Y denotes a suitableleaving group,and, if required, subsequently converting the resultingcompound I into a salt thereof, or comprises, if required, subsequentlyliberating the compound I from a resulting salt of the compound I.
 7. Apharmaceutical composition containing, in a suitable carrier, aneffective amount of a compound as claimed in claim 1 and/or apharmacologically compatible salt thereof.
 8. A method for preventing ortreating a gastrointestinal disorder which comprises administering aneffective amount of a compound of claim 1 or a pharmacologicallycompatible salt thereof to one subject to or afflicted with suchdisorder.
 9. In the compounding of a pharmaceutical compositioncomprising a suitable carrier and an essential active component forpreventing or treating a gastrointestinal disorder, the improvementwherein the active component is a compound of claim 1 or apharmacologically compatible salt thereof.